Tamiflu PI

8/14/2019 Tamiflu PI

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TAMIFLU

(oseltamivir phosphate)

CAPSULES

AND FOR ORAL SUSPENSION

Rx only

DESCRIPTION

TAMIFLU (oseltamivir phosphate) is available as capsules containing 30 mg, 45 mg, or 75 mg

oseltamivir for oral use, in the form of oseltamivir phosphate, and as a powder for oral suspension,

which when constituted with water as directed contains 12 mg/mL oseltamivir base. In addition to theactive ingredient, each capsule contains pregelatinized starch, talc, povidone K 30, croscarmellose

sodium, and sodium stearyl fumarate. The 30 mg capsule shell contains gelatin, titanium dioxide,

yellow iron oxide, and red iron oxide. The 45 mg capsule shell contains gelatin, titanium dioxide, and

black iron oxide. The 75 mg capsule shell contains gelatin, titanium dioxide, yellow iron oxide, black

iron oxide, and red iron oxide. Each capsule is printed with blue ink, which includes FD&C Blue No. 2

as the colorant. In addition to the active ingredient, the powder for oral suspension contains sorbitol,

monosodium citrate, xanthan gum, titanium dioxide, tutti-frutti flavoring, sodium benzoate, and

saccharin sodium.

Oseltamivir phosphate is a white crystalline solid with the chemical name (3R,4R,5S)-4-acetylamino-

5-amino-3(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid, ethyl ester, phosphate (1:1). Thechemical formula is C16H28N2O4 (free base). The molecular weight is 312.4 for oseltamivir free base

and 410.4 for oseltamivir phosphate salt. The structural formula is as follows:

34

5

NH2

COOC2H5O

NH

OH

3PO

4.

MICROBIOLOGY

Mechanism of Action

Oseltamivir phosphate is an ethyl ester prodrug requiring ester hydrolysis for conversion to the active

form, oseltamivir carboxylate. Oseltamivir carboxylate is an inhibitor of influenza virus neuraminidase

affecting release of viral particles.


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Antiviral Activity

The antiviral activity of oseltamivir carboxylate against laboratory strains and clinical isolates of

influenza virus was determined in cell culture assays. The concentrations of oseltamivir carboxylate

required for inhibition of influenza virus were highly variable depending on the assay method used andthe virus tested. The 50% and 90% effective concentrations (EC50 and EC90) were in the range of

0.0008 M to >35 M and 0.004 M to >100 M, respectively (1 M=0.284 g/mL). The relationship

between the antiviral activity in cell culture and the inhibition of influenza virus replication in humans

has not been established.

Resistance

Influenza A virus isolates with reduced susceptibility to oseltamivir carboxylate have been recovered

by serial passage of virus in cell culture in the presence of increasing concentrations of oseltamivir

carboxylate. Genetic analysis of these isolates showed that reduced susceptibility to oseltamivir

carboxylate is associated with mutations that result in amino acid changes in the viral neuraminidase orviral hemagglutinin or both. Resistance substitutions selected in cell culture in neuraminidase are

I222T and H274Y in influenza A N1 and I222T and R292K in influenza A N2. Substitutions E119V,

R292K and R305Q have been selected in avian influenza A neuraminidase N9. Substitutions A28T

and R124M have been selected in the hemagglutinin of influenza A H3N2 and substitution H154Q in

the hemagglutinin of a reassortant human/avian virus H1N9.

In clinical studies in the treatment of naturally acquired infection with influenza virus, 1.3% (4/301) of

posttreatment isolates in adult patients and adolescents, and 8.6% (9/105) in pediatric patients aged 1

to 12 years showed emergence of influenza variants with decreased neuraminidase susceptibility in cell

culture to oseltamivir carboxylate. Substitutions in influenza A neuraminidase resulting in decreased

susceptibility were H274Y in neuraminidase N1 and E119V and R292K in neuraminidase N2.Insufficient information is available to fully characterize the risk of emergence of TAMIFLU

resistance in clinical use.

In clinical studies of postexposure and seasonal prophylaxis, determination of resistance by population

nucleotide sequence analysis was limited by the low overall incidence rate of influenza infection and

prophylactic effect of TAMIFLU.

Cross-resistance

Cross-resistance between zanamivir-resistant influenza mutants and oseltamivir-resistant influenza

mutants has been observed in cell culture. Due to limitations in the assays available to detect drug-

induced shifts in virus susceptibility, an estimate of the incidence of oseltamivir resistance and possiblecross-resistance to zanamivir in clinical isolates cannot be made. However, two of the three

oseltamivir-induced substitutions (E119V, H274Y and R292K) in the viral neuraminidase from clinical

isolates occur at the same amino acid residues as two of the three substitutions (E119G/A/D, R152K

and R292K) observed in zanamivir-resistant virus.


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Immune Response

No influenza vaccine interaction study has been conducted. In studies of naturally acquired and

experimental influenza, treatment with TAMIFLU did not impair normal humoral antibody response to

infection.

CLINICAL PHARMACOLOGY

Pharmacokinetics

Absorption and Bioavailability

Oseltamivir is readily absorbed from the gastrointestinal tract after oral administration of oseltamivir

phosphate and is extensively converted predominantly by hepatic esterases to oseltamivir carboxylate.

At least 75% of an oral dose reaches the systemic circulation as oseltamivir carboxylate. Exposure to

oseltamivir is less than 5% of the total exposure after oral dosing (see Table 1).

Table 1 Mean (% CV) Pharmacokinetic Parameters of Oseltamivir andOseltamivir Carboxylate After a Multiple 75 mg Capsule Twice Daily OralDose (n=20)

Parameter OseltamivirOseltamivir

Carboxylate

Cmax (ng/mL) 65.2 (26) 348 (18)

AUC0-12h(ngh/mL) 112 (25) 2719 (20)

Plasma concentrations of oseltamivir carboxylate are proportional to doses up to 500 mg given twice

daily (see DOSAGE AND ADMINISTRATION).Coadministration with food has no significant effect on the peak plasma concentration (551 ng/mL

under fasted conditions and 441 ng/mL under fed conditions) and the area under the plasma

concentration time curve (6218 ngh/mL under fasted conditions and 6069 ngh/mL under fed

conditions) of oseltamivir carboxylate.

Distribution

The volume of distribution (Vss) of oseltamivir carboxylate, following intravenous administration in 24

subjects, ranged between 23 and 26 liters.

The binding of oseltamivir carboxylate to human plasma protein is low (3%). The binding of

oseltamivir to human plasma protein is 42%, which is insufficient to cause significant displacement-based drug interactions.

Metabolism

Oseltamivir is extensively converted to oseltamivir carboxylate by esterases located predominantly in

the liver. Neither oseltamivir nor oseltamivir carboxylate is a substrate for, or inhibitor of, cytochrome

P450 isoforms.


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Elimination

Absorbed oseltamivir is primarily (>90%) eliminated by conversion to oseltamivir carboxylate. Plasma

concentrations of oseltamivir declined with a half-life of 1 to 3 hours in most subjects after oral

administration. Oseltamivir carboxylate is not further metabolized and is eliminated in the urine.Plasma concentrations of oseltamivir carboxylate declined with a half-life of 6 to 10 hours in most

subjects after oral administration. Oseltamivir carboxylate is eliminated entirely (>99%) by renal

excretion. Renal clearance (18.8 L/h) exceeds glomerular filtration rate (7.5 L/h) indicating that tubular

secretion occurs, in addition to glomerular filtration. Less than 20% of an oral radiolabeled dose is

eliminated in feces.

Special Populations

Renal Impairment

Administration of 100 mg of oseltamivir phosphate twice daily for 5 days to patients with various

degrees of renal impairment showed that exposure to oseltamivir carboxylate is inversely proportional

to declining renal function. Oseltamivir carboxylate exposures in patients with normal and abnormal

renal function administered various dose regimens of oseltamivir are described in Table 2.

Table 2 Oseltamivir Carboxylate Exposures in Patients With Normal andReduced Serum Creatinine Clearance

Parameter Normal Renal Function Impaired Renal Function

75 mg

qd

75 mg

bid

150 mg

bid

Creatinine Clearance

10 and


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Geriatric Patients

Exposure to oseltamivir carboxylate at steady-state was 25% to 35% higher in geriatric patients (age

range 65 to 78 years) compared to young adults given comparable doses of oseltamivir. Half-lives

observed in the geriatric patients were similar to those seen in young adults. Based on drug exposureand tolerability, dose adjustments are not required for geriatric patients for either treatment or

prophylaxis (see DOSAGE AND ADMINISTRATION: Special Dosage Instructions).

INDICATIONS AND USAGE

Treatment of Influenza

TAMIFLU is indicated for the treatment of uncomplicated acute illness due to influenza infection in

patients 1 year and older who have been symptomatic for no more than 2 days.

Prophylaxis of Influenza

TAMIFLU is indicated for the prophylaxis of influenza in patients 1 year and older.

TAMIFLU is not a substitute for early vaccination on an annual basis as recommended by the Centers

for Disease Control and Prevention Advisory Committee on Immunization Practices.

Description of Clinical Studies: Studies in Naturally Occurring Influenza


Adult Patients

Two phase III placebo-controlled and double-blind clinical trials were conducted: one in the USA and

one outside the USA. Patients were eligible for these trials if they had fever >100F, accompanied by atleast one respiratory symptom (cough, nasal symptoms or sore throat) and at least one systemic

symptom (myalgia, chills/sweats, malaise, fatigue or headache) and influenza virus was known to be

circulating in the community. In addition, all patients enrolled in the trials were allowed to take fever-

reducing medications.

Of 1355 patients enrolled in these two trials, 849 (63%) patients were influenza-infected (age range 18

to 65 years; median age 34 years; 52% male; 90% Caucasian; 31% smokers). Of the 849 influenza-

infected patients, 95% were infected with influenza A, 3% with influenza B, and 2% with influenza of

unknown type.

TAMIFLU was started within 40 hours of onset of symptoms. Subjects participating in the trials were

required to self-assess the influenza-associated symptoms as none, mild, moderate or severe.

Time to improvement was calculated from the time of treatment initiation to the time when all

symptoms (nasal congestion, sore throat, cough, aches, fatigue, headaches, and chills/sweats) were

assessed as none or mild. In both studies, at the recommended dose of TAMIFLU 75 mg twice

daily for 5 days, there was a 1.3 day reduction in the median time to improvement in influenza-infected

subjects receiving TAMIFLU compared to subjects receiving placebo. Subgroup analyses of these

studies by gender showed no differences in the treatment effect of TAMIFLU in men and women.

In the treatment of influenza, no increased efficacy was demonstrated in subjects receiving treatment of

150 mg TAMIFLU twice daily for 5 days.


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Geriatric Patients

Three double-blind placebo-controlled treatment trials were conducted in patients 65 years of age in

three consecutive seasons. The enrollment criteria were similar to that of adult trials with the exception

of fever being defined as >97.5F. Of 741 patients enrolled, 476 (65%) patients were influenza-infected. Of the 476 influenza-infected patients, 95% were infected with influenza type A and 5% with

influenza type B.

In the pooled analysis, at the recommended dose of TAMIFLU 75 mg twice daily for 5 days, there was

a 1 day reduction in the median time to improvement in influenza-infected subjects receiving

TAMIFLU compared to those receiving placebo (p=NS). However, the magnitude of treatment effect

varied between studies.

Pediatric Patients

One double-blind placebo-controlled treatment trial was conducted in pediatric patients aged 1 to 12

years (median age 5 years), who had fever (>100F) plus one respiratory symptom (cough or coryza)when influenza virus was known to be circulating in the community. Of 698 patients enrolled in this

trial, 452 (65%) were influenza-infected (50% male; 68% Caucasian). Of the 452 influenza-infected

patients, 67% were infected with influenza A and 33% with influenza B.

The primary endpoint in this study was the time to freedom from illness, a composite endpoint which

required 4 individual conditions to be met. These were: alleviation of cough, alleviation of coryza,

resolution of fever, and parental opinion of a return to normal health and activity. TAMIFLU treatment

of 2 mg/kg twice daily, started within 48 hours of onset of symptoms, significantly reduced the total

composite time to freedom from illness by 1.5 days compared to placebo. Subgroup analyses of this

study by gender showed no differences in the treatment effect of TAMIFLU in males and females.


Adult Patients

The efficacy of TAMIFLU in preventing naturally occurring influenza illness has been demonstrated

in three seasonal prophylaxis studies and a postexposure prophylaxis study in households. The primary

efficacy parameter for all these studies was the incidence of laboratory-confirmed clinical influenza.

Laboratory-confirmed clinical influenza was defined as oral temperature 99.0F/37.2C plus at least

one respiratory symptom (cough, sore throat, nasal congestion) and at least one constitutional symptom

(aches and pain, fatigue, headache, chills/sweats), all recorded within 24 hours, plus either a positive

virus isolation or a fourfold increase in virus antibody titers from baseline.

In a pooled analysis of two seasonal prophylaxis studies in healthy unvaccinated adults (aged 13 to 65

years), TAMIFLU 75 mg once daily taken for 42 days during a community outbreak reduced the

incidence of laboratory-confirmed clinical influenza from 4.8% (25/519) for the placebo group to 1.2%

(6/520) for the TAMIFLU group.

In a seasonal prophylaxis study in elderly residents of skilled nursing homes, TAMIFLU 75 mg once

daily taken for 42 days reduced the incidence of laboratory-confirmed clinical influenza from 4.4%

(12/272) for the placebo group to 0.4% (1/276) for the TAMIFLU group. About 80% of this elderly

population were vaccinated, 14% of subjects had chronic airway obstructive disorders, and 43% had

cardiac disorders.


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In a study of postexposure prophylaxis in household contacts (aged 13 years) of an index case,

TAMIFLU 75 mg once daily administered within 2 days of onset of symptoms in the index case and

continued for 7 days reduced the incidence of laboratory-confirmed clinical influenza from 12%

(24/200) in the placebo group to 1% (2/205) for the TAMIFLU group. Index cases did not receiveTAMIFLU in the study.

Pediatric Patients

The efficacy of TAMIFLU in preventing naturally occurring influenza illness has been demonstrated

in a randomized, open-label, postexposure prophylaxis study in households that included children aged

1 to 12 years, both as index cases and as family contacts. All index cases in this study received

treatment. The primary efficacy parameter for this study was the incidence of laboratory-confirmed

clinical influenza in the household. Laboratory-confirmed clinical influenza was defined as oral

temperature 100F/37.8C plus cough and/or coryza recorded within 48 hours, plus either a positive

virus isolation or a fourfold or greater increase in virus antibody titers from baseline or at illness visits.

Among household contacts 1 to 12 years of age not already shedding virus at baseline, TAMIFLU for

Oral Suspension 30 mg to 60 mg taken once daily for 10 days reduced the incidence of laboratory-

confirmed clinical influenza from 17% (18/106) in the group not receiving prophylaxis to 3% (3/95) in

the group receiving prophylaxis.

CONTRAINDICATIONS

TAMIFLU is contraindicated in patients with known hypersensitivity to any of the components of the

product.

PRECAUTIONS

General

There is no evidence for efficacy of TAMIFLU in any illness caused by agents other than influenza

viruses Types A and B.

Use of TAMIFLU should not affect the evaluation of individuals for annual influenza vaccination in

accordance with guidelines of the Centers for Disease Control and Prevention Advisory Committee on

Immunization Practices.

Efficacy of TAMIFLU in patients who begin treatment after 40 hours of symptoms has not been

established.

Efficacy of TAMIFLU in the treatment of subjects with chronic cardiac disease and/or respiratory

disease has not been established. No difference in the incidence of complications was observedbetween the treatment and placebo groups in this population. No information is available regarding

treatment of influenza in patients with any medical condition sufficiently severe or unstable to be

considered at imminent risk of requiring hospitalization.

Safety and efficacy of repeated treatment or prophylaxis courses have not been studied.

Efficacy of TAMIFLU for treatment or prophylaxis has not been established in immunocompromised

patients.


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Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as

complications during the course of influenza. TAMIFLU has not been shown to prevent such

complications.

Hepatic Impairment

The safety and pharmacokinetics in patients with severe hepatic impairment have not been evaluated

(see DOSAGE AND ADMINISTRATION).

Renal Impairment

Dose adjustment is recommended for patients with a serum creatinine clearance


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A bottle of 13 g TAMIFLU for Oral Suspension contains approximately 11 g sorbitol. One dose of 75

mg TAMIFLU for Oral Suspension delivers 2 g sorbitol. For patients with hereditary fructose

intolerance, this is above the daily maximum limit of sorbitol and may cause dyspepsia and diarrhea.

Drug Interactions

The concurrent use of TAMIFLU with live attenuated influenza vaccine (LAIV) intranasal has not

been evaluated. However, because of the potential for interference between these products, LAIV

should not be administered within 2 weeks before or 48 hours after administration of TAMIFLU,

unless medically indicated. The concern about possible interference arises from the potential for

antiviral drugs to inhibit replication of live vaccine virus. Trivalent inactivated influenza vaccine can

be administered at any time relative to use of TAMIFLU.

Information derived from pharmacology and pharmacokinetic studies of oseltamivir suggests that

clinically significant drug interactions are unlikely.

Oseltamivir is extensively converted to oseltamivir carboxylate by esterases, located predominantly in

the liver. Drug interactions involving competition for esterases have not been extensively reported in

literature. Low protein binding of oseltamivir and oseltamivir carboxylate suggests that the probability

of drug displacement interactions is low.

In vitro studies demonstrate that neither oseltamivir nor oseltamivir carboxylate is a good substrate for

P450 mixed-function oxidases or for glucuronyl transferases.

Clinically important drug interactions involving competition for renal tubular secretion are unlikely

due to the known safety margin for most of these drugs, the elimination characteristics of oseltamivir

carboxylate (glomerular filtration and anionic tubular secretion) and the excretion capacity of these

pathways. Coadministration of probenecid results in an approximate twofold increase in exposure tooseltamivir carboxylate due to a decrease in active anionic tubular secretion in the kidney. However,

due to the safety margin of oseltamivir carboxylate, no dose adjustments are required when

coadministering with probenecid.

No pharmacokinetic interactions have been observed when coadministering oseltamivir with

amoxicillin, acetaminophen, cimetidine or with antacids (magnesium and aluminum hydroxides and

calcium carbonates).

Carcinogenesis, Mutagenesis, and Impairment of Fertility

In 2-year carcinogenicity studies in mice and rats given daily oral doses of the pro-drug oseltamivirphosphate up to 400 mg/kg and 500 mg/kg, respectively, the pro-drug oseltamivir phosphate and the

active form oseltamivir carboxylate induced no statistically significant increases in tumors over

controls. The mean maximum daily exposures to the prodrug in mice and rats were approximately 130-

and 320-fold, respectively, greater than those in humans at the proposed clinical dose based on AUC

comparisons. The respective safety margins of the exposures to the active oseltamivir carboxylate were

15- and 50-fold.

Oseltamivir was found to be non-mutagenic in the Ames test and the human lymphocyte chromosome

assay with and without enzymatic activation and negative in the mouse micronucleus test. It was found

to be positive in a Syrian Hamster Embryo (SHE) cell transformation test. Oseltamivir carboxylate was


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non-mutagenic in the Ames test and the L5178Y mouse lymphoma assay with and without enzymatic

activation and negative in the SHE cell transformation test.

In a fertility and early embryonic development study in rats, doses of oseltamivir at 50, 250, and 1500

mg/kg/day were administered to females for 2 weeks before mating, during mating and until day 6 of

pregnancy. Males were dosed for 4 weeks before mating, during and for 2 weeks after mating. There

were no effects on fertility, mating performance or early embryonic development at any dose level.

The highest dose was approximately 100 times the human systemic exposure (AUC0-24h) of oseltamivir

carboxylate.

Pregnancy

Pregnancy Category C

There are insufficient human data upon which to base an evaluation of risk of TAMIFLU to the

pregnant woman or developing fetus. Studies for effects on embryo-fetal development were conducted

in rats (50, 250, and 1500 mg/kg/day) and rabbits (50, 150, and 500 mg/kg/day) by the oral route.

Relative exposures at these doses were, respectively, 2, 13, and 100 times human exposure in the rat

and 4, 8, and 50 times human exposure in the rabbit. Pharmacokinetic studies indicated that fetal

exposure was seen in both species. In the rat study, minimal maternal toxicity was reported in the 1500

mg/kg/day group. In the rabbit study, slight and marked maternal toxicities were observed,

respectively, in the 150 and 500 mg/kg/day groups. There was a dose-dependent increase in the

incidence rates of a variety of minor skeletal abnormalities and variants in the exposed offspring in

these studies. However, the individual incidence rate of each skeletal abnormality or variant remained

within the background rates of occurrence in the species studied.

Because animal reproductive studies may not be predictive of human response and there are noadequate and well-controlled studies in pregnant women, TAMIFLU should be used during pregnancy

only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

In lactating rats, oseltamivir and oseltamivir carboxylate are excreted in the milk. It is not known

whether oseltamivir or oseltamivir carboxylate is excreted in human milk. TAMIFLU should,

therefore, be used only if the potential benefit for the lactating mother justifies the potential risk to the

breast-fed infant.

Geriatric Use

The safety of TAMIFLU has been established in clinical studies which enrolled 741 subjects (374

received placebo and 362 received TAMIFLU). Some seasonal variability was noted in the clinical

efficacy outcomes (see INDICATIONS AND USAGE:Description of Clinical Studies: Studies in

Naturally Occurring Influenza: Treatment of Influenza:Geriatric Patients).

Safety and efficacy have been demonstrated in elderly residents of nursing homes who took TAMIFLU

for up to 42 days for the prevention of influenza. Many of these individuals had cardiac and/or

respiratory disease, and most had received vaccine that season (see INDICATIONS AND USAGE:


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Description of Clinical Studies: Studies in Naturally Occurring Influenza: Prophylaxis of

Influenza: Adult Patients).

Pediatric Use

The safety and efficacy of TAMIFLU in pediatric patients younger than 1 year of age have not been

studied. TAMIFLU is not indicated for either treatment or prophylaxis of influenza in pediatric

patients younger than 1 year of age because of uncertainties regarding the rate of development of the

human blood-brain barrier and the unknown clinical significance of non-clinical animal toxicology

data for human infants (see ANIMAL TOXICOLOGY).

ANIMAL TOXICOLOGY

In a 2-week study in unweaned rats, administration of a single dose of 1000 mg/kg oseltamivir

phosphate to 7-day-old rats resulted in deaths associated with unusually high exposure to the prodrug.

However, at 2000 mg/kg, there were no deaths or other significant effects in 14-day-old unweaned rats.

Further follow-up investigations of the unexpected deaths of 7-day-old rats at 1000 mg/kg revealedthat the concentrations of the prodrug in the brains were approximately 1500-fold those of the brains of

adult rats administered the same oral dose of 1000 mg/kg, and those of the active metabolite were

approximately 3-fold higher. Plasma levels of the prodrug were 10-fold higher in 7-day-old rats as

compared with adult rats. These observations suggest that the levels of oseltamivir in the brains of rats

decrease with increasing age and most likely reflect the maturation stage of the blood-brain barrier. No

adverse effects occurred at 500 mg/kg/day administered to 7- to 21-day-old rats. At this dosage, the

exposure to prodrug was approximately 800-fold the exposure expected in a 1-year-old child.

ADVERSE REACTIONS

Treatment Studies in Adult PatientsA total of 1171 patients who participated in adult phase III controlled clinical trials for the treatment of

influenza were treated with TAMIFLU. The most frequently reported adverse events in these studies

were nausea and vomiting. These events were generally of mild to moderate degree and usually

occurred on the first 2 days of administration. Less than 1% of subjects discontinued prematurely from

clinical trials due to nausea and vomiting.

Adverse events that occurred with an incidence of1% in 1440 patients taking placebo or TAMIFLU

75 mg twice daily in adult phase III treatment studies are shown in Table 3. This summary includes

945 healthy young adults and 495 at risk patients (elderly patients and patients with chronic cardiac

or respiratory disease). Those events reported numerically more frequently in patients taking

TAMIFLU compared with placebo were nausea, vomiting, bronchitis, insomnia, and vertigo.

Prophylaxis Studies in Adult Patients

A total of 4187 subjects (adolescents, healthy adults and elderly) participated in phase III prophylaxis

studies, of whom 1790 received the recommended dose of 75 mg once daily for up to 6 weeks.

Adverse events were qualitatively very similar to those seen in the treatment studies, despite a longer

duration of dosing (see Table 3). Events reported more frequently in subjects receiving TAMIFLU

compared to subjects receiving placebo in prophylaxis studies, and more commonly than in treatment

studies, were aches and pains, rhinorrhea, dyspepsia and upper respiratory tract infections. However,

the difference in incidence between TAMIFLU and placebo for these events was less than 1%. There


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were no clinically relevant differences in the safety profile of the 942 elderly subjects who received

TAMIFLU or placebo, compared with the younger population.

Table 3 Most Frequent Adverse Events in Studies in Naturally AcquiredInfluenza in Patients 13 Years of Age and Older

Treatment Prophylaxis

Adverse Event

Placebo

N=716

Oseltamivir

75 mg bid

N=724

Placebo/

No

Prophylaxisa

N=1688

Oseltamivir

75 mg qd

N=1790

Nausea (without vomiting) 40 (6%) 72 (10%) 56 (3%) 129 (7%)

Vomiting 21 (3%) 68 (9%) 16 (1%) 39 (2%)

Diarrhea 70 (10%) 48 (7%) 40 (2%) 50 (3%)

Bronchitis 15 (2%) 17 (2%) 22 (1%) 15 (1%)

Abdominal pain 16 (2%) 16 (2%) 25 (1%) 37 (2%)

Dizziness 25 (3%) 15 (2%) 21 (1%) 24 (1%)

Headache 14 (2%) 13 (2%) 306 (18%) 326 (18%)

Cough 12 (2%) 9 (1%) 119 (7%) 94 (5%)

Insomnia 6 (1%) 8 (1%) 15 (1%) 22 (1%)

Vertigo 4 (1%) 7 (1%) 4 (


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Prophylaxis in Pediatric Patients

Pediatric patients aged 1 to 12 years participated in a postexposure prophylaxis study in households,

both as index cases (134) and as contacts (222). Gastrointestinal events were the most frequent,

particularly vomiting. The adverse events noted were consistent with those previously observed inpediatric treatment studies (see Table 4).

Table 4 Most Frequent Adverse Events Occurring in Children Aged 1 to 12Years in Studies in Naturally Acquired Influenza

Treatment Trialsa

Household Prophylaxis Trialb

Adverse Event

Placebo

N=517

Oseltamivir

2 mg/kg bid

N=515

No

Prophylaxisc

N=87

Prophylaxis

with

Oseltamivir

QDc

N=99

Vomiting 48 (9%) 77 (15%) 2 (2%) 10 (10%)

Diarrhea 55 (11%) 49 (10%) - 1 (1%)

Otitis media 58 (11%) 45 (9%) 2 (2%) 2 (2%)

Abdominal pain 20 (4%) 24 (5%) - 3 (3%)

Asthma (including

aggravated)

19 (4%) 18 (3%) 1 (1%) 1 (1%)

Nausea 22 (4%) 17 (3%) 1 (1%) 4 (4%)

Epistaxis 13 (3%) 16 (3%) - 1 (1%)

Pneumonia 17 (3%) 10 (2%) 2 (2%) -Ear disorder 6 (1%) 9 (2%) - -

Sinusitis 13 (3%) 9 (2%) - -

Bronchitis 11 (2%) 8 (2%) 2 (2%) -

Conjunctivitis 2 (


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Observed During Clinical Practice

The following adverse reactions have been identified during postmarketing use of TAMIFLU. Because

these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably

estimate their frequency or establish a causal relationship to TAMIFLU exposure.

Body as a Whole: Swelling of the face or tongue, allergy, anaphylactic/anaphylactoid reactions

Dermatologic: Dermatitis, rash, eczema, urticaria, erythema multiforme, Stevens-Johnson Syndrome,

toxic epidermal necrolysis (see PRECAUTIONS)

Digestive: Hepatitis, liver function tests abnormal

Cardiac: Arrhythmia

Gastrointestinal disorders: Gastrointestinal bleeding, hemorrhagic colitis

Neurologic: Seizure

Metabolic: Aggravation of diabetes

Psychiatric: Delirium, including symptoms such as altered level of consciousness, confusion, abnormal

behavior, delusions, hallucinations, agitation, anxiety, nightmares (see PRECAUTIONS)

OVERDOSAGE

At present, there has been no experience with overdose. Single doses of up to 1000 mg of TAMIFLU

have been associated with nausea and/or vomiting.

DOSAGE AND ADMINISTRATION

TAMIFLU may be taken with or without food (see CLINICAL PHARMACOLOGY:

Pharmacokinetics). However, when taken with food, tolerability may be enhanced in some patients.

Standard Dosage Treatment of Influenza

Adults and Adolescents

The recommended oral dose of TAMIFLU for treatment of influenza in adults and adolescents 13

years and older is 75 mg twice daily for 5 days. Treatment should begin within 2 days of onset of

symptoms of influenza.

Pediatric Patients

TAMIFLU is not indicated for treatment of influenza in pediatric patients younger than 1 year.

The recommended oral dose of TAMIFLU for pediatric patients 1 year and older is shown in Table 5.

TAMIFLU for Oral Suspension may also be used by patients who cannot swallow a capsule. For

pediatric patients who cannot swallow capsules, TAMIFLU for Oral Suspension is the preferred

formulation. If the for Oral Suspension product is not available, TAMIFLU Capsules may be opened

and mixed with sweetened liquids such as regular or sugar-free chocolate syrup.


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Table 5 Oral Dose of TAMIFLU for Treatment of Influenza in Pediatric Patientsby Weight

Body Weight

(kg)

Body Weight

(lbs)

Recommended Dose

for 5 Days

Number of Bottles of

TAMIFLU for Oral

Suspension Needed

to Obtain the

Recommended Doses

for a 5 Day Regimen

Number of TAMIFLU

Capsules Needed to

Obtain the

Recommended Doses

for a 5 Day Regimen

15 kg 33 lbs 30 mg twice daily 1 10 TAMIFLU Capsules

(30 mg)

>15 kg to 23 kg >33 lbs to 51 lbs 45 mg twice daily 2 10 TAMIFLU Capsules

(45 mg)

>23 kg to 40 kg >51 lbs to 88 lbs 60 mg twice daily 2 20 TAMIFLU Capsules

(30 mg)

>40 kg >88 lbs 75 mg twice daily 3 10 TAMIFLU Capsules

(75 mg)

An oral dosing dispenser with 30 mg, 45 mg, and 60 mg graduations is provided with the oral

suspension; the 75 mg dose can be measured using a combination of 30 mg and 45 mg. It is

recommended that patients use this dispenser. In the event that the dispenser provided is lost or

damaged, another dosing syringe or other device may be used to deliver the following volumes:

2.5 mL (1/2 tsp) for children 15 kg, 3.8 mL (3/4 tsp) for >15 to 23 kg, 5.0 mL (1 tsp) for >23 to 40

kg, and 6.2 mL (1 1/4 tsp) for >40 kg.

Standard Dosage Prophylaxis of Influenza

Adults and Adolescents

The recommended oral dose of TAMIFLU for prophylaxis of influenza in adults and adolescents 13

years and older following close contact with an infected individual is 75 mg once daily for at least 10

days. Therapy should begin within 2 days of exposure. The recommended dose for prophylaxis during

a community outbreak of influenza is 75 mg once daily. Safety and efficacy have been demonstrated

for up to 6 weeks. The duration of protection lasts for as long as dosing is continued.

Pediatric Patients

The safety and efficacy of TAMIFLU for prophylaxis of influenza in pediatric patients younger than 1

year of age have not been established.

The recommended oral dose of TAMIFLU for pediatric patients 1 year and older following close

contact with an infected individual is shown in Table 6. TAMIFLU for Oral Suspension may also be

used by patients who cannot swallow a capsule. For pediatric patients who cannot swallow capsules,

TAMIFLU for Oral Suspension is the preferred formulation. If the for Oral Suspension product is not

available, TAMIFLU Capsules may be opened and mixed with sweetened liquids such as regular or

sugar-free chocolate syrup.


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Table 6 Oral Dose of TAMIFLU for Prophylaxis of Influenza in Pediatric Patientsby Weight

Body Weight

(kg)

Body Weight

(lbs)

Recommended

Dose for

10 Days

Number of Bottles of

TAMIFLU for Oral

Suspension Needed to

Obtain the

Recommended Doses

for a 10 Day Regimen

Number of TAMIFLU

Capsules Needed to

Obtain the

Recommended Doses

for a 10 Day Regimen

15 kg 33 lbs 30 mg once

daily

1 10 TAMIFLU Capsules

(30 mg)

>15 kg to 23 kg >33 lbs to 51 lbs 45 mg once

daily


(45 mg)

>23 kg to 40 kg >51 lbs to 88 lbs 60 mg once

daily


(30 mg)

>40 kg >88 lbs 75 mg once

daily


(75 mg)

An oral dosing dispenser with 30 mg, 45 mg, and 60 mg graduations is provided with the oral

suspension; the 75 mg dose can be measured using a combination of 30 mg and 45 mg. It is

recommended that patients use this dispenser. In the event that the dispenser provided is lost or

damaged, another dosing syringe or other device may be used to deliver the following volumes:

2.5 mL (1/2 tsp) for children 15 kg, 3.8 mL (3/4 tsp) for >15 to 23 kg, 5.0 mL (1 tsp) for >23 to 40

kg, and 6.2 mL (1 1/4 tsp) for >40 kg.

Prophylaxis in pediatric patients following close contact with an infected individual is recommended

for 10 days. Prophylaxis in patients 1 to 12 years of age has not been evaluated for longer than 10 days

duration. Therapy should begin within 2 days of exposure.

Special Dosage Instructions

Hepatic Impairment

No dose adjustment is recommended for patients with mild or moderate hepatic impairment (Child-

Pugh score 9) (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations).

Renal Impairment

For plasma concentrations of oseltamivir carboxylate predicted to occur following various dosing

schedules in patients with renal impairment, see CLINICAL PHARMACOLOGY:

Pharmacokinetics: Special Populations.


Dose adjustment is recommended for patients with creatinine clearance between 10 and 30 mL/min

receiving TAMIFLU for the treatment of influenza. In these patients it is recommended that the dose


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be reduced to 75 mg of TAMIFLU once daily for 5 days. No recommended dosing regimens are

available for patients undergoing routine hemodialysis and continuous peritoneal dialysis treatment

with end-stage renal disease.


For the prophylaxis of influenza, dose adjustment is recommended for patients with creatinine

clearance between 10 and 30 mL/min receiving TAMIFLU. In these patients it is recommended that

the dose be reduced to 75 mg of TAMIFLU every other day or 30 mg TAMIFLU every day. No

recommended dosing regimens are available for patients undergoing routine hemodialysis and

continuous peritoneal dialysis treatment with end-stage renal disease.

Geriatric Patients

No dose adjustment is required for geriatric patients (see CLINICAL PHARMACOLOGY:

Pharmacokinetics:Special Populations and PRECAUTIONS).

Preparation of TAMIFLU for Oral Suspension

It is recommended that TAMIFLU for Oral Suspension be constituted by the pharmacist prior to

dispensing to the patient:

1. Tap the closed bottle several times to loosen the powder.

2. Measure 23 mL of water in a graduated cylinder.

3. Add the total amount of water for constitution to the bottle and shake the closed bottle well for 15seconds.

4. Remove the child-resistant cap and push bottle adapter into the neck of the bottle.

5. Close bottle with child-resistant cap tightly. This will assure the proper seating of the bottle adapterin the bottle and child-resistant status of the cap.

NOTE: SHAKE THE TAMIFLU FOR ORAL SUSPENSION WELL BEFORE EACH USE.

The constituted TAMIFLU for Oral Suspension (12 mg/mL) should be used within 10 days of

preparation; the pharmacist should write the date of expiration of the constituted suspension on a

pharmacy label. The patient package insert and oral dispenser should be dispensed to the patient.

Emergency Compounding of an Oral Suspension from TAMIFLU Capsules(Final Concentration 15 mg/mL)

The following directions are provided for use only during emergency situations. These directions are

not intended to be used if the FDA-approved, commercially manufactured TAMIFLU for Oral

Suspension is readily available from wholesalers or the manufacturer.

Compounding an oral suspension with this procedure will provide one patient with enough medication

for a 5-day course of treatment or a 10-day course of prophylaxis.


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Commercially manufactured TAMIFLU for Oral Suspension (12 mg/mL) is the preferred product for

pediatric and adult patients who have difficulty swallowing capsules or where lower doses are needed.

In the event that TAMIFLU for Oral Suspension is not available, the pharmacist may compound a

suspension (15 mg/mL) from TAMIFLU (oseltamivir phosphate) Capsules 75 mg using either of twovehicles: Cherry Syrup (Humco) or Ora-Sweet SF (sugar-free) (Paddock Laboratories). Other

vehicles have not been studied. This compounded suspension should not be used for convenience

or when the FDA-approved TAMIFLU for Oral Suspension is commercially available.

First, calculate the Total Volume of an oral suspension needed to be compounded and dispensed for

each patient. The Total Volume required is determined by the weight of each patient. Refer to Table

7.

Table 7 Volume of an Oral Suspension (15 mg/mL) Needed to be CompoundedBased Upon the Patients Weight

Body Weight (kg) Body Weight (lbs) Total Volume to Compoundper patient (mL)

15 kg 33 lbs 30 mL

16 to 23 kg 34 to 51 lbs 40 mL

24 to 40 kg 52 to 88 lbs 50 mL

41 kg 89 lbs 60 mL

Second, determine the number of capsules and the amount of vehicle (Cherry Syrup or Ora-Sweet SF)that are needed to prepare the Total Volume (calculated from Table 7: 30 mL, 40 mL, 50 mL, or 60

mL) of compounded oral suspension (15 mg/mL). Refer to Table 8.

Table 8 Number of TAMIFLU 75 mg Capsules and Amount of Vehicle (CherrySyrup OR Ora-Sweet SF) Needed to Prepare the Total Volume of aCompounded Oral Suspension (15 mg/mL)

Total Volume of

Compounded Oral

Suspension needed to be

Prepared

30 mL 40 mL 50 mL 60 mL

Required number of

TAMIFLU 75 mg

Capsules

6 capsules

(450 mg

oseltamivir)

8 capsules

(600 mg

oseltamivir)

10 capsules

(750 mg

oseltamivir)

12 capsules

(900 mg

oseltamivir)

Required volume of

vehicle

Cherry Syrup (Humco) OR

Ora-Sweet SF (Paddock

29 mL 38.5 mL 48 mL 57 mL


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Laboratories)

Third, follow the procedure below for compounding the oral suspension (15 mg/mL) from TAMIFLUCapsules 75 mg

1. Carefully separate the capsule body and cap and transfer the contents of the required number ofTAMIFLU 75 mg Capsules into a clean mortar.

2. Triturate the granules to a fine powder.

3. Add one-third (1/3) of the specified amount of vehicle and triturate the powder until a uniformsuspension is achieved.

4. Transfer the suspension to an amber glass or amber polyethyleneterephthalate (PET) bottle. Afunnel may be used to eliminate any spillage.

5. Add another one-third (1/3) of the vehicle to the mortar, rinse the pestle and mortar by a trituratingmotion and transfer the vehicle into the bottle.

6. Repeat the rinsing (Step 5) with the remainder of the vehicle.

7. Close the bottle using a child-resistant cap.

8. Shake well to completely dissolve the active drug and to ensure homogeneous distribution of thedissolved drug in the resulting suspension. (Note: The active drug, oseltamivir phosphate, readily

dissolves in the specified vehicles. The suspension is caused by some of the inert ingredients of

TAMIFLU Capsules which are insoluble in these vehicles.)

9. Put an ancillary label on the bottle indicating Shake Gently Before Use. [This compoundedsuspension should be gently shaken prior to administration to minimize the tendency for air

entrapment, particularly with the Ora-Sweet SF preparation.]

10.Instruct the parent or guardian that any remaining material following completion of therapy mustbe discarded by either affixing an ancillary label to the bottle or adding a statement to the

pharmacy label instructions.

11.Place an appropriate expiration date label according to storage condition (see below).

STORAGE OF THE PHARMACY-COMPOUNDED SUSPENSION:

Refrigeration: Stable for 5 weeks (35 days) when stored in a refrigerator at 2 to 8C (36 to 46F).

Room Temperature: Stable for five days (5 days) when stored at room temperature, 25C (77F).

Note: The storage conditions are based on stability studies of compounded oral suspensions, using the

above mentioned vehicles, which were placed in amber glass and amber polyethyleneterephthalate(PET) bottles. Stability studies have not been conducted with other vehicles or bottle types.

Place a pharmacy label on the bottle that includes the patients name, dosing instructions, and drug

name and any other required information to be in compliance with all State and Federal Pharmacy

Regulations. Refer to Table 9 for the proper dosing instructions.

Note: This compounding procedure results in a 15 mg/mL suspension, which is different from

the commercially available TAMIFLU for Oral Suspension, which has a concentration of 12

mg/mL.


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Table 9 Dosing Chart for Pharmacy-Compounded Suspension from TAMIFLUCapsules 75 mg

Body

Weight(kg)

Body

Weight(lbs)

Dose

(mg)

Volume

per Dose15 mg/mL

Treatment

Dose (for 5days)

Prophylaxis

Dose (for10 days)

15 kg 33 lbs 30 mg 2 mL 2 mL two

times a day

2 mL once

daily

16 to 23

kg

34 to 51

lbs

45 mg 3 mL 3 mL two

times a day

3 mL once

daily

24 to 40

kg

52 to 88

lbs

60 mg 4 mL 4 mL two

times a day

4 mL once

daily

41 kg 89 lbs 75 mg 5 mL 5 mL twotimes a day

5 mL oncedaily

Note: 1 teaspoon = 5 mL

Consider dispensing the suspension with a graduated oral syringe for measuring small amounts of

suspension. If possible, mark or highlight the graduation corresponding to the appropriate dose (2

mL, 3 mL, 4 mL, or 5 mL) on the oral syringe for each patient. The dosing device dispensed with the

commercially available TAMIFLU for Oral Suspension should NOT be used with the compounded

suspension since they have different concentrations.

HOW SUPPLIED

TAMIFLU Capsules

30-mg capsules (30 mg free base equivalent of the phosphate salt): light yellow hard gelatin capsules.

"ROCHE" is printed in blue ink on the light yellow body and "30 mg" is printed in blue ink on the light

yellow cap. Available in blister packages of 10 (NDC 0004-0802-85).

45-mg capsules (45 mg free base equivalent of the phosphate salt): grey hard gelatin capsules.

"ROCHE" is printed in blue ink on the grey body and "45 mg" is printed in blue ink on the grey cap.

Available in blister packages of 10 (NDC 0004-0801-85).

75-mg capsules (75 mg free base equivalent of the phosphate salt): grey/light yellow hard gelatin

capsules. "ROCHE" is printed in blue ink on the grey body and "75 mg" is printed in blue ink on the

light yellow cap. Available in blister packages of 10 (NDC 0004-0800-85).

Storage

Store the capsules at 25C (77F); excursions permitted to 15 to 30C (59 to 86F). [See USP

Controlled Room Temperature]

TAMIFLU for Oral Suspension

Supplied as a white powder blend for constitution to a white tutti-fruttiflavored suspension. Available

in glass bottles containing approximately 33 mL of suspension after constitution. Each bottle delivers


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25 mL of suspension equivalent to 300 mg oseltamivir base. Each bottle is supplied with a bottle

adapter and 1 oral dispenser (NDC 0004-0810-95).

StorageStore dry powder at 25C (77F); excursions permitted to 15 to 30C (59 to 86F). [See USP

Controlled Room Temperature]

Store constituted suspension under refrigeration at 2 to 8C (36 to 46F). Do not freeze.

Humco is a registered trademark of Humco Holding Group, Inc.

Ora-Sweet SF is a registered trademark of Paddock Laboratories

Distributed by:

Licensor:

Gilead Sciences, Inc.

Foster City, California 94404

xxxxxxxx

Rev. January, 2008

Copyright 1999-200x by Roche Laboratories Inc. All rights reserved.


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Patient Information

TAMIFLU

(oseltamivir phosphate)

RX ONLY

This leaflet contains important information about TAMIFLU (TAM-ih-flew). Read it well before you

begin treatment. This information does not take the place of talking with your healthcare professional

about your medical condition or your treatment. This leaflet does not list all the benefits and risks of

TAMIFLU. If you have any questions about TAMIFLU, ask your healthcare professional. Only your

healthcare professional can determine if TAMIFLU is right for you.

What is TAMIFLU?

TAMIFLU attacks the influenza virus and stops it from spreading inside your body. TAMIFLU treats

flu at its source, by attacking the virus that causes the flu, rather than simply masking symptoms.

TAMIFLU is for treating adults and children age 1 and older with the flu whose flu symptoms started

within the last day or two. TAMIFLU can also reduce the chance of getting the flu in people age 1 and

older who have a higher chance of getting the flu because they spend time with someone who has the

flu. TAMIFLU can also reduce the chance of getting the flu if there is a flu outbreak in the community.

What is Flu?The flu is an infection caused by the influenza virus. Flu symptoms include fever (usually 100F to

103F in adults, and sometimes higher in children) and problems such as cough, sore throat, runny or

stuffy nose, headaches, muscle aches, fever, and extreme tiredness. Many people use the term flu to

mean any combination of these symptoms, such as the common cold, but true influenza infection is

often worse and may last longer than a cold.

Flu outbreaks happen about once a year, usually in the winter, when the influenza virus spreads widely

in the community. Outside of those outbreaks, only a very tiny number of respiratory infections are

caused by the influenza virus.

Should I get a flu shot?TAMIFLU is not a substitute for a flu vaccination. You should continue to get a flu vaccination every

year, according to your healthcare professionals advice.

Who should not take TAMIFLU?

Do not take TAMIFLU if you are allergic to the main ingredient, oseltamivir phosphate, or to any

other ingredients of TAMIFLU. Before starting treatment, make sure your healthcare professional

knows if you take any other medicines, or are pregnant, planning to become pregnant, or breastfeeding.

TAMIFLU is normally not recommended for use during pregnancy or nursing, as the effects on the


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unborn child or nursing infant are unknown. TAMIFLU is not recommended for use in children

younger than 1 year of age.

Tell your healthcare professional if you have any type of kidney disease, heart disease, respiratory

disease, or any serious health condition.

TAMIFLU for Oral Suspension contains sorbitol. Sorbitol may cause upset stomach and diarrhea in

patients with a family history of fructose intolerance.

How should I take TAMIFLU?

It is important that you begin your treatment with TAMIFLU as soon as possible from the first

appearance of your flu symptoms or soon after you are exposed to the flu. If you feel worse or develop

new symptoms during treatment with TAMIFLU, or if your flu symptoms do not start to get better,

you should contact your healthcare professional.

If you have the flu: Take TAMIFLU twice a day for 5 days, once in the morning and once in the

evening. You should complete the entire treatment of 10 doses (capsules or suspension), even if you

feel better.

To prevent the flu: If someone in your home has the flu, take TAMIFLU once a day for 10 days or for

as long as prescribed. You can take TAMIFLU for up to 6 weeks if you are exposed to the flu because

of an outbreak in your community. Follow your healthcare professionals advice on how long to take

TAMIFLU.

TAMIFLU has not been studied in children 1 to 12 years of age for preventing flu during an outbreak

in your community or for use for more than 10 days.

You can take TAMIFLU with food or without food. There is less chance of stomach upset if you take

it with a light snack, milk, or a meal.

If you are taking TAMIFLU for Oral Suspension, your pharmacist will give you a dosing dispenser

marked with three possible doses. Follow your healthcare professionals instructions on which dose to

take or how to combine them for the proper dose for you. In order to be sure you receive the proper

dose, it is important that you use the dispenser provided. Review the instructions below on how to use

the dispenser and ask your pharmacist if you have any questions. If you lose or damage the dispenser

and cannot use it, contact your healthcare professional or pharmacist for advice on the proper dose.

If TAMIFLU for Oral Suspension is not available, your healthcare provider may instruct you to open

TAMIFLU Capsules and mix the contents with sweetened liquids such as regular or sugar-freechocolate syrup. Please follow the dosing instructions below.

If you forget to take your medicine, take the missed dose as soon as you remember, except if it is 2

hours or less before your next dose. Then continue to take TAMIFLU at the usual times. Do not take 2

doses at a time to make up for a missed dose. If you miss several doses, tell your healthcare

professional and follow the advice given to you.


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What are the possible side effects of TAMIFLU?

The most common side effects of TAMIFLU are nausea and vomiting. These are usually mild to

moderate. They usually happen in the first 2 days of treatment. Taking TAMIFLU with food may

reduce the chance of getting these side effects.

If you develop an allergic reaction or severe rash, stop taking TAMIFLU and contact your healthcare

professional.

People with the flu, particularly children and adolescents, may be at an increased risk of seizures,

confusion, or abnormal behavior early during their illness. These events may occur shortly after

beginning TAMIFLU or may occur when flu is not treated. These events are uncommon but may result

in accidental injury to the patient. Therefore, patients should be observed for signs of unusual behavior

and a healthcare professional should be contacted immediately if the patient shows any signs of

unusual behavior.

Before taking TAMIFLU, please let your healthcare provider know if you have received nasallyadministered influenza virus vaccine during the past two weeks.

If you notice any side effects not mentioned in this leaflet, or if you have any concerns about the side

effects you get, tell your healthcare professional.

How and where should I store TAMIFLU?

TAMIFLU Capsules should be stored at room temperature, 77F (25C) and kept in a dry place. Keep

this medication out of reach of children.

TAMIFLU for Oral Suspension should be stored under refrigeration at 36 to 46F (2 to 8C). Do not

freeze.

General advice about prescription medicines:

Medicines are sometimes prescribed for conditions that are not mentioned in patient information

leaflets. Do not use TAMIFLU for a condition for which it was not prescribed. Do not give TAMIFLU

to other people, even if they have the same symptoms you have. It may not be right for them.

This leaflet summarizes the most important information about TAMIFLU. If you would like more

information, talk with your healthcare professional. You can ask your pharmacist or healthcare

professional for information about TAMIFLU that is written for health professionals.

DOSING INSTRUCTIONS FOR PATIENTS:

How Do I Prepare TAMIFLU for Oral Suspension?

Please follow instructions carefully to ensure proper dosing of the oral suspension.


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Shake closed bottle well for about 5 seconds before each use.

Remove child-resistant cap.

Before inserting the tip of the oral dispenser into bottle adapter, push the plunger completely downtoward the tip of the oral dispenser. Insert tip firmly into opening of the bottle adapter.

Turn the entire unit (bottle and oral dispenser) upside down.

Pull the plunger out slowly until the desired amount of medication is withdrawn into the oraldispenser (see figure). The 75 mg dose is obtained by filling the dispenser twice, once to the 30 mg

graduation, and a second fill to the 45 mg graduation.

Turn the entire unit right side up and remove the oral dispenser slowly from the bottle.

Dispense directly into mouth. Do not mix with any liquid prior to dispensing.

Close bottle with child-resistant cap after each use.

Disassemble oral dispenser, rinse under running tap water and air dry prior to next use.

If Directed by My Healthcare Provider, How Do I Mix the Contents of TAMIFLU Capsules with

Sweetened Liquids?

Please follow instructions carefully to ensure proper dosing.

Holding one capsule over a small bowl, carefully pull the capsule open and pour the completecontents of the capsule into the bowl.

Add a small amount of a sweetened liquid such as chocolate syrup (regular or sugar-free) that thechild will consume completely.

Stir the mixture and give the entire dose to the child.


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Distributed by:

Licensor:

Gilead Sciences, Inc.

Foster City, California 94404

Rev. January, 2008

Copyright 1999-200x by Roche Laboratories Inc. All rights reserved.

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